RESUMEN
The histology of signet-ring cell carcinoma (SRC) of the stomach has been revisited with the support of current immuno- histochemical techniques in order to explain particular features of this tumor; its great capacity of local diffusion and lymph node metastasis, also through a neo-lymphoangiogenesis. An observational retrospective study on 50 cases of SRC in stage II and III has been performed with the addition of histochemical (Alcian Blue, DDD-Fast Blue B, Mercury Orange) and immunohistochemical (cytocheratin, CD3, CD4, CD8, CD10, CD56, CD68, perforin, granzyme B, podoplanin, collagen type IV) investigations for each case. The signet ring cells, typical for this tumor, show abundant content of electro-negative sialomucins and demonstrate a great capacity of diffusion through the gastric wall. They evoke production and deposition of collagen type IV in the sub-mucosa layer through the local action of fibroblasts. The immunological response to this tumor in the gastric wall and in the metastatic lymph nodes is represented by an increase of B and T-helper lymphocytes, but not of T-killers or natural killers. The neoplastic cells are curiously able to avoid these newly formed 'lymph nodules'. An extended neo-lymphangiogenesis has been observed around the primary tumor and in metastatic lymph nodes. A careful immunohistochemical characterization has allowed a better knowledge of SRC, regarding especially the peculiar behavior of local diffusion of its cells, the associated neo-lymph angiogenesis, and poor immunological reaction.
Asunto(s)
Carcinoma de Células en Anillo de Sello/patología , Neoplasias Gástricas/patología , Linfocitos B/inmunología , Carcinoma de Células en Anillo de Sello/inmunología , Humanos , Inmunohistoquímica , Metástasis Linfática , Estudios Retrospectivos , Neoplasias Gástricas/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
BACKGROUND: MOC31PE immunotoxin was developed to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule, which is highly expressed in colorectal cancer. Although cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may offer long-term survival to patients with peritoneal metastasis from colorectal cancer (PM-CRC), most patients experience disease relapse and novel therapeutic options are needed. On this basis, MOC31PE is being developed as a novel therapeutic principle to target PM-CRC. METHODS: This was a dose-escalating phase I trial to evaluate the safety and toxicity (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon intraperitoneal administration of MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with Mitomycin C. Fifteen patients received the study drug at four dose levels (3+3+3+6), administered intraperitoneally as a single dose the day after CRS-HIPEC. RESULTS: No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. There was negligible systemic absorption of the study drug. Drug concentrations in peritoneal fluid samples were in the cytotoxic range and increased in a dose-dependent manner. MOC31PE recovered from peritoneal cavity retained its cytotoxic activity in cell-based assays. All patients developed neutralizing antibodies. CONCLUSIONS: Intraperitoneal administration of MOC31PE was safe and well tolerated, and combined with low systemic uptake, MOC31PE seems ideal for local intraperitoneal treatment. The drug will be further evaluated in an ongoing phase II expansion cohort.
Asunto(s)
Carcinoma de Células en Anillo de Sello/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Neoplasias Peritoneales/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/patología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunoconjugados/farmacocinética , Inyecciones Intraperitoneales , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias Peritoneales/inmunología , Neoplasias Peritoneales/patología , Pronóstico , Tasa de Supervivencia , Distribución TisularRESUMEN
BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is associated with a poor prognosis in many cancers but the biological mechanisms involved are unknown. Since cytokines and angiogenic factors (CAFs) are reflected by various immune responses, we analyzed the association between the NLR and CAFs and their prognostic implications in gastric cancer (GC). METHODS: Of 745 GC patients who were enrolled in NLR analysis, 70 underwent NLR and CAF association analyses. Pretreatment serum levels of 52 CAFs were measured by means of multiplex bead immunoassays and enzyme-linked immunosorbent assays. Linear regression analysis and survival analysis of the NLR with each CAF were performed. RESULTS: Metastatic organ numbers and carbohydrate antigen 19-9 levels were significantly higher in patients with a high NLR [greater than 2.42 (median): P = 0.047 and P < 0.001 respectively]. The overall survival was significantly worse in the high NLR group (17.8 months vs 11.2 months, P < 0.001). In CAF analysis, osteopontin (R 2 = 0.337, P < 0.001) and interleukin-6 (R 2 = 0.141, P = 0.001) were significantly associated with the NLR. Stromal-cell-derived factor 1 (SDF-1) was a significant poor prognostic factor independently of the NLR. Consideration of both the NLR and SDF-1 divided patient groups with different overall survival (both low, 21.0 months; either high, 15.8 months; both high, 8.2 months). CONCLUSION: The NLR is a significant poor prognostic factor in advanced GC. The NLR is mainly associated with osteopontin and interleukin-6. Besides the NLR, SDF-1 is an independent poor prognostic factor in GC. Consideration of both the NLR and SDF-1 might give insights into antitumor immunity in GC.
Asunto(s)
Inductores de la Angiogénesis/sangre , Citocinas/sangre , Linfocitos/patología , Recurrencia Local de Neoplasia/inmunología , Neutrófilos/patología , Neoplasias Gástricas/inmunología , Adenocarcinoma/sangre , Adenocarcinoma/inmunología , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Células en Anillo de Sello/sangre , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/secundario , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias Gástricas/sangre , Neoplasias Gástricas/patología , Tasa de Supervivencia , Adulto JovenAsunto(s)
Carcinoma de Células en Anillo de Sello/inmunología , Gastritis/inmunología , Queratinas/metabolismo , Células Plasmáticas/patología , Carcinoma de Células en Anillo de Sello/diagnóstico , Carcinoma de Células en Anillo de Sello/patología , Diagnóstico Diferencial , Endoscopía Gastrointestinal/métodos , Mucosa Gástrica/patología , Gastritis/diagnóstico , Gastritis/patología , HumanosRESUMEN
Childhood onset of colorectal signet-ring cell carcinoma (CR-SRCC) is extremely rare and featured as highly malignant with poor prognosis. Here we reported a CR-SRCC case of 11-year-old boy with a novel inherited X-linked KDM6AA694T mutation. The H3K27me3 demethylase KDM6A was frequently mutated in varieties of tumors and acts as a tumor suppressor. In vivo H3K27me3 demethylation assay demonstrated that KDM6AA694T had dampened H3K27me3 demethylase activity. Overexpression of KDM6AA694T in SRCC cell line KATO3 promoted cell proliferation, invasion and migration, which were further confirmed in vivo by constructing orthotopic tumor growth and lung metastasis model. Besides, expression of KDM6AA694T in immune cells suppresses inflammatory macrophage response and effector T cell response. In conclusion, we characterized a novel inherited KDM6AA694T mutant from a childhood-onset SRCC case and demonstrated that the mutant with impaired H3K27me3 demethylase activity could potentiate tumor malignancy and suppress antitumor immunity.
Asunto(s)
Carcinoma de Células en Anillo de Sello , Neoplasias Colorrectales , Histona Demetilasas , Niño , Humanos , Masculino , Carcinoma de Células en Anillo de Sello/genética , Carcinoma de Células en Anillo de Sello/patología , Carcinoma de Células en Anillo de Sello/inmunología , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/inmunología , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Mutación , Escape del Tumor/genéticaRESUMEN
BACKGROUND: It was recently reported that the transcription factor Forkhead box P3 (FoxP3) is expressed not only in regulatory T cells (Tregs) but also in cancer cells. The aim of this study was to clarify the clinical significance of FoxP3 expression in gastric carcinoma. METHODS: We performed immunohistochemical staining of FoxP3 to examine the association of FoxP3 expression with clinicopathological features of 194 patients with gastric cancer who underwent surgical resection from 2000 to 2010. We also investigated the immunosuppressive function of FoxP3 using gastric cancer cell lines. RESULTS: Immunohistochemical staining indicated FoxP3-positive cells within tumour tissue including both Tregs and tumour cells. Forkhead box P3-positive tumour cells were observed in 79.3% of signet ring cell carcinoma patients, and the expression of FoxP3 showed a significant correlation with lymph node metastasis. We showed that transforming growth factor-ß augmented FoxP3 mRNA expression in cell lines derived from signet ring cell carcinoma. Indoleamine-2,3-dioxygenase and galectin-1, key effectors of Treg-mediated immunosuppression, were downregulated by FoxP3 knockdown. CONCLUSION: Our findings suggested that FoxP3 expression by tumour cells might have important roles in immune escape of gastric carcinoma, and be associated with the malignant potential of scirrhous gastric carcinoma.
Asunto(s)
Carcinoma de Células en Anillo de Sello/inmunología , Factores de Transcripción Forkhead/fisiología , Neoplasias Gástricas/inmunología , Carcinoma de Células en Anillo de Sello/química , Carcinoma de Células en Anillo de Sello/patología , Línea Celular Tumoral , Factores de Transcripción Forkhead/análisis , Factores de Transcripción Forkhead/genética , Humanos , Tolerancia Inmunológica , Inmunohistoquímica , ARN Mensajero/análisis , Neoplasias Gástricas/química , Neoplasias Gástricas/patología , Linfocitos T Reguladores/inmunología , Escape del TumorRESUMEN
BACKGROUND: Isolated cancer cells of non-solid type poorly differentiated adenocarcinoma (por2) or signet-ring cell carcinoma (sig) are frequently seen in scirrhous gastric cancers with a very poor prognosis. These cells are often scattered in granulation tissue or desmoplastic fibrotic tissue and tend to be overlooked in routine pathological examination. We aimed to raise a novel antibody that can identify the isolated cancer cells easily. METHODS: Because the MUC1 cytoplasmic tail domain (CTD) has many biological roles including tumor progression and cell adhesion disturbance and is expected to be expressed in isolated cancer cells, we raised a novel monoclonal antibody (MAb) MUC1-014E against an intracellular nonrepeating 19-amino-acid sequence (RYVPPSSTDRSPYEKVSAG: N-1217-1235-C) of the MUC1 CTD, using a synthetic peptide including the 7-amino-acid epitope (STDRSPY: N-1223-1229-C). RESULTS: In the immunohistochemical staining of 107 gastrectomy specimens including 48 por2 and 31 sig lesions, the MAb MUC1-014E showed high rates of positive staining (≥5% of carcinoma cells stained) for por2 (100%) and sig (97%), and of the highest intensity staining (4+, ≥75% of carcinoma cells stained) for por2 (100%) and sig (90%). In the 89 biopsy specimens including 82 por2 and 38 sig lesions, the MAb MUC1-014E showed high rates of positive staining for por2 (100%) and sig (100%) and of 4+ staining for por2 (87%) and sig (84%). All the rates were significantly higher than those with cytokeratins (AE1/AE3 or CAM5.2). CONCLUSIONS: The MAb MUC1-014E is very useful for accurate detection of isolated cancer cells in scirrhous gastric cancers.
Asunto(s)
Adenocarcinoma/patología , Inmunohistoquímica/métodos , Mucina-1/inmunología , Neoplasias Gástricas/patología , Adenocarcinoma/inmunología , Adenocarcinoma/cirugía , Adenocarcinoma Escirroso/inmunología , Adenocarcinoma Escirroso/patología , Adenocarcinoma Escirroso/cirugía , Secuencia de Aminoácidos , Anticuerpos Monoclonales/inmunología , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/patología , Carcinoma de Células en Anillo de Sello/cirugía , Diferenciación Celular , Citoplasma/inmunología , Citoplasma/patología , Gastrectomía , Mucosa Gástrica/citología , Mucosa Gástrica/inmunología , Humanos , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/cirugíaRESUMEN
Colorectal signet ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer (CRC) with unique characteristics. Due to the limited researches on it, a comprehensive and in-depth understanding of this subtype is still lacking. In this article, we summarize the clinicopathological features and molecular characteristics of colorectal SRCC based on a literature review. Clinically, SRCC has been associated with young age, proximal site preference, advanced tumor stage, high histological grade, high rate of lymph node involvement, frequent peritoneal metastasis, and a significantly poor prognosis. Regarding molecular characteristics, in SRCC, the mutation burden of the classic signaling pathways that include WNT/ß-catenin, RAS/RAF/MAPK, and PI3K/AKT/mTOR signaling pathways are generally reduced. In contrast, some genes related to the "epithelial-mesenchymal transition (EMT) process" and the "stem cell properties", including RNF43, CDH1, and SMAD4, as well as the related TGF-ß signaling pathway have been observed more frequently altered in SRCC than in conventional adenocarcinoma (AC). In many studies but not in others, SRCC showed a higher frequency of BRAF mutation, microsatellite instability-high (MSI-H) and CpG island methylator phenotype (CIMP) positive status compared to AC. It has been proposed that colorectal SRCC consists of two subtypes, in which the MSI+/CIMP+/BRAF +/CD3+/PD-L1+ hypermethylated genotype is more common in the proximal colon, and may represent the potential candidate for immunotherapy. Understanding the special molecular mechanisms related to the aggressive biology of SRCC is of great importance, which may provide a theoretical basis for the development of more targeted and effective treatments for this refractory disease.
Asunto(s)
Carcinoma de Células en Anillo de Sello/genética , Carcinoma de Células en Anillo de Sello/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Proteína de la Poliposis Adenomatosa del Colon/genética , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/terapia , Neoplasias Colorrectales/metabolismo , Terapia Combinada , Islas de CpG , Metilación de ADN , Inestabilidad Genómica , Humanos , Mutación , Pronóstico , Recto/patología , Transducción de Señal/genéticaRESUMEN
RATIONALE: Advanced signet ring cell (SRC) carcinoma has a worse prognosis. Therefore, early diagnosis and prevention is particularly important; SRC tumors have lower R0 resection rate and are thought to be less chemosensitive than non-SRCC. Consequently, a novel postoperative adjuvant treatment is urgently needed to improve clinical outcomes. PATIENT CONCERNS: A 41-year-old female with advanced gastric SRC carcinoma was treated with radical gastrectomy and oxaliplatin-based regimen for 6 cycles after surgery. She was suspected of recurrence with the high level of carbohydrate antigen (CA) 72-4. DIAGNOSES: The gastroscopy revealed SRC carcinoma of gastric antrum and poorly differentiated adenocarcinoma in some areas. The diagnosis of postoperative pathology report was gastric cancer with stage III C (T4a, N3a, M0). INTERVENTIONS: The level of CA72-4 rapidly increased during the 2 follow-up after the completion of conventional treatment, ex vivo-cultured allogeneic natural killer (NK) cell infusion was offered to prevent recurrence. OUTCOMES: Intravenous injections of NK cells combination with surgical treatment and chemotherapy showed therapeutic effects in this patient with possible relapse. The patient remained disease-free 46âmonths after the infusion of NK cells until the latest follow-up. LESSONS: CA72-4 appeared to be the most sensitive and specific marker in the gastric cancer patient, and the high level of CA72-4 may indicate the risk of recurrence. This case report provide rationale for NK cell infusion following the rapid increase of CA72-4 to prevent recurrence.
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Carcinoma de Células en Anillo de Sello/terapia , Gastrectomía , Células Asesinas Naturales/trasplante , Cuidados Posoperatorios/métodos , Neoplasias Gástricas/terapia , Adulto , Antígenos de Carbohidratos Asociados a Tumores/sangre , Antígenos de Carbohidratos Asociados a Tumores/inmunología , Carcinoma de Células en Anillo de Sello/diagnóstico , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/patología , Terapia Combinada/métodos , Femenino , Humanos , Estadificación de Neoplasias , Pronóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Recently, there have been a few reports of rituximab (RTX)-induced Crohn's disease, but there is no literature available on successful long-term treatment and the clinical outcome of this condition. We retrospectively analyzed the clinical data of a rare case of Crohn's disease induced by RTX administered as induction and prolonged maintenance therapy of a follicular lymphoma, diagnosed synchronously with a gastric signet ring cells carcinoma, treated at our hospital.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Enfermedad de Crohn/inmunología , Rituximab/efectos adversos , Budesonida/uso terapéutico , Carcinoma de Células en Anillo de Sello/diagnóstico , Carcinoma de Células en Anillo de Sello/tratamiento farmacológico , Carcinoma de Células en Anillo de Sello/inmunología , Enfermedad de Crohn/inducido químicamente , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Quimioterapia Combinada/métodos , Humanos , Quimioterapia de Inducción/efectos adversos , Quimioterapia de Inducción/métodos , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/inmunología , Quimioterapia de Mantención/efectos adversos , Quimioterapia de Mantención/métodos , Masculino , Mesalamina/uso terapéutico , Persona de Mediana Edad , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias Primarias Múltiples/inmunología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/inmunología , Resultado del TratamientoRESUMEN
Recent data supports a potentially significant role for immune checkpoint inhibitors in the treatment of gastric cancer. However, there are few data on the clinical implications of immunotherapy markers in gastric signet-ring cell carcinoma (SRCC). We evaluated the expression of programmed cell death protein-1 (PD-1), programmed cell death ligand 1(PD-L1), infiltration by CD3+ T cell, microsatellite instability (MSI), and Epstein-Barr Virus (EBV), and the relationship of each factor to survival in 89 advanced SRCC patients. All patients received 5-FU-based first-line chemotherapy. PD-L1 and PD-1 were expressed in 40.4% and 18.0% of the patients, respectively. There was a significant correlation between PD-L1 and PD-1 expression (r=0.363, p<0.001). There was loss of at least 1 of the 4 DNA mismatch repair (DNA-MMR) gene proteins in 32.6% of samples. Only 1 case out of 89 was EBV positive, with concurrent PD-L1 positivity, a high degree of CD3+ T cell infiltration and MSI. Increased CD3+ T cells numbers was associated with increased PD-1 expression (r=0.256, p=0.012) and MSI status (r=0.208, p=0.049). High CD3+ T cell infiltration was related to better OS (23.7 months, 95% CI: 19.0-38.0 vs 15.8 months, 95% CI: 13.0-22.0, p=0.033), but was not an independent prognostic factor for survival after multivariate analysis (HR=0.68, 95% CI: 0.42-1.10, p=0.116). CD3+ T cell was more infiltrated in PD-1 positive, tumors with MSI and were associated with better OS, indicating an adaptive immune resistance may be occurring. Further research into the cancer immunotherapy markers of SRCC immune microenvironment may highlight targets for immunotherapy.
Asunto(s)
Biomarcadores de Tumor/inmunología , Carcinoma de Células en Anillo de Sello/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Gástricas/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/análisis , Complejo CD3/inmunología , Carcinoma de Células en Anillo de Sello/mortalidad , Carcinoma de Células en Anillo de Sello/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunoterapia , Estimación de Kaplan-Meier , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/biosíntesis , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Microambiente Tumoral/inmunologíaRESUMEN
Primary signet ring stromal tumor of the testis (PSRSTT) is an extremely rare tumor described only twice in the literature. Pancreatic-analogue solid pseudopapillary neoplasm (SPN) of the testis is a recently reported entity with morphological overlap with PSRSTT. We reviewed our files to find all cases of PSRSTT to better characterize this entity. We studied 13 cases of PSRSTTs using histological, immunohistochemical (IHC), and molecular genetic methods and compared the results with pancreatic SPN. Grossly, the size of PSRSTTs ranged from 0.5 to 2 cm (mean 1.1). Microscopically, PSRSTTs predominantly showed a proliferation of low-grade epithelioid cells containing characteristic cytoplasmic vacuole dislodging the nucleus (signet ring cells) separated by fibrous septa into trabeculae and nests. The immunoprofile was characterized by immunoreactivity for ß-catenin, cyclin D1 (nuclear positivity for both antibodies), CD10, vimentin, galectin-3, claudin 7, α-1-antitrypsin, CD56, and neuron-specific enolase and negativity for chromogranin, inhibin, calretinin, SF-1, NANOG, OCT3/4, and SALL4. In some cases, the IHC panel was restricted because of a limited amount of tissue. Molecular genetic analysis revealed mutations within exon 3 of the CTNNB1 encoding ß-catenin in all analyzable cases. Based on histological similarities between pancreatic SPN and PSRSTT and their identical IHC and molecular genetic features, we assume that both neoplasms share the same pathogenesis, and thus, PSRSTT can be considered as a testicular analogue of pancreatic SPN.
Asunto(s)
Carcinoma de Células en Anillo de Sello , Neoplasias Pancreáticas , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Neoplasias Testiculares , Adulto , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biopsia , Carcinoma de Células en Anillo de Sello/química , Carcinoma de Células en Anillo de Sello/genética , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/patología , Diferenciación Celular , Linaje de la Célula , Proliferación Celular , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Fenotipo , Tumores de los Cordones Sexuales y Estroma de las Gónadas/química , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/inmunología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasias Testiculares/química , Neoplasias Testiculares/genética , Neoplasias Testiculares/inmunología , Neoplasias Testiculares/patología , Adulto Joven , beta Catenina/análisis , beta Catenina/genéticaRESUMEN
Primary cutaneous signet ring cell carcinoma (PCSRCC) is a very unusual but distinctive clinicopathologic entity that can simulate metastatic adenocarcinomas. It is defined as a diffuse malignant epithelial neoplasia localized in the dermis and subcutis without epidermal involvement, showing variable amounts of signet ring cells, without evidence of visceral adenocarcinoma. We present 2 cases of PCSRCC, which involved eyelids and axilla respectively. Despite thorough systemic workup, primary sources could not be demonstrated in either case. The tumor cells are positive for gross cystic disease fluid protein 15 in addition to a variety of glandular markers. Furthermore, both cases were immunostained with cytokeratin 20 (CK20). In conclusion, we report 2 cases of PCSRCC expressing CK20 immunoreactivity. CK20-positive primary cutaneous tumors should include PCSRCC in addition to Merkel cell carcinoma.
Asunto(s)
Carcinoma de Células en Anillo de Sello/inmunología , Queratinas/inmunología , Neoplasias Cutáneas/inmunología , Anciano , Humanos , Queratina-20 , Masculino , Persona de Mediana EdadRESUMEN
Recent human tumor immunology research has identified several genes coding immunogenic peptides recognized by CD8 cytotoxic T lymphocytes (CTLs) in melanoma tumors. Very recently, CD4 T cell antigenic epitopes were also determined in certain melanoma tumors. The use of these peptides in conjunction with human immunotherapy could prove to be of great benefit. However, such peptides in clinically common tumors of epithelial cell origin, such as of the stomach, colon, lung, etc., have not yet been determined extensively. We describe for the first time an HLA-A31 (A*31012)-restricted natural antigenic peptide recognized by the CD8 CTL TcHST-2 of gastric signet ring cell carcinoma cell line HST-2. We also identified the HLA-DRB1*08032-restricted peptide recognized by the CD4 T cell line TcOSC-20 of squamous cell carcinoma OSC-20 derived from the oral cavity. The antigenic peptide of HST-2, designated F4.2, is composed of 10 amino acid residues with two anchor motif residues necessary for binding to HLA-A31 molecules. The synthetic F4.2 peptide enhanced the reactivity of TcHST-2 against HST-2 cells. Furthermore, introduction of an expression minigene coding F4.2 peptide to HLA-A31(+) cells conferred cytotoxic susceptibility to TcHST-2 on the cells. Some stomach cancer lines into which the HLA-A31 gene had been introduced, such as MKN28-A31-2, were lysed by TcHST-2, suggesting the presence of F4.2 peptide in at least some HLA-A31(+) stomach cancers. Furthermore, F4.2 peptide induced an F4.2 peptide-specific CTL response in at least 30-40% of HLA-A31(+) peripheral blood lymphocytes from gastric cancer patients, suggesting that F4.2 peptide could be used as a cancer vaccine for gastric tumors. The natural antigenic peptide of OSC-20 was also determined using acid extraction and biochemical separation and by mass spectrometry. Consequently, OSC-20 peptide was designated as the 6-1-5 peptide, an HLA-DRB1*08032-restricted 16-mer peptide with two possible anchor motifs. It has an amino acid sequence identical to that of human alpha-enolase, suggesting that it was derived from the processed parental alpha-enolase protein. We are presently attempting to determine the genes that code tumor rejection antigens recognized by HLA-A24- and A26-restricted T cells, including those of pulmonary and pancreatic carcinomas. The search for these antigenic peptides may lead to the identification of immunogenic peptide antigens that would be suitable for clinical use in commonly occurring epithelial cancers.
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Antígenos de Neoplasias/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito T/inmunología , Fragmentos de Péptidos , Secuencia de Aminoácidos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/farmacología , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células Escamosas/inmunología , Antígenos HLA-A/inmunología , Antígenos HLA-DR/inmunología , Subtipos Serológicos HLA-DR , Humanos , Datos de Secuencia Molecular , Neoplasias de la Boca/inmunología , Neoplasias Gástricas/inmunología , Células Tumorales CultivadasRESUMEN
CONTEXT: The expression of membrane-bound complement regulatory proteins (mCRPs) that inhibit the complement system in normal tissues is essential for self-protection against an autologous immune reaction. However, the expression patterns of mCRPs, including CD46, CD55, and CD59, are inconsistent in different types of cancer cells. OBJECTIVES: To determine whether CD46, CD55, and CD59 are differentially expressed in neoplastic and adjacent normal colon tissues and to assess their clinical significance. DESIGN: Immunohistochemistry was performed on tissue microarrays of cancerous and adjacent normal colon tissues. RESULTS: The expression levels of CD46, CD55, and CD59 were significantly higher in colon cancer tissues compared with the normal adjacent colon tissues. We found that the expression levels of CD55 and CD59 correlated with the grade of differentiation in colon cancers. In addition, the expression of CD55 and CD59 was greater in stage III and stage IV colon cancers than in stage I and stage II cancers according to staging by the TNM classification. CONCLUSIONS: CD46, CD55, and CD59 are up-regulated in colon cancer. Specifically, CD55 and CD59 are of clinical relevance to differentiation and TNM staging of colon cancer. These data suggest that CD46, CD55, and CD59 have the potential to be used for molecular staging diagnoses and for colon cancer therapies.
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Antígenos CD55/metabolismo , Antígenos CD59/metabolismo , Neoplasias del Colon/inmunología , Proteína Cofactora de Membrana/metabolismo , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adenocarcinoma Mucinoso/inmunología , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/patología , Colon/inmunología , Neoplasias del Colon/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valores de Referencia , Análisis de Matrices Tisulares , Regulación hacia ArribaRESUMEN
Appendiceal tumors exhibiting both neuroendocrine and glandular differentiation are uncommon and have caused difficulty in pathologic classification, prediction of prognosis, and clinical management. Previously, such lesions have been variously designated as adenocarcinoid, goblet cell carcinoid (GCC), and mixed adenocarcinoma carcinoid. In this study, we undertook a retrospective investigation of 63 such cases and classified them as typical GCC (group A) and adenocarcinoma ex GCC on the basis of the histologic features of the tumor at the primary site. The adenocarcinoma ex GCC group was further divided into signet ring cell type (group B) and poorly differentiated adenocarcinoma type (group C). The clinical characteristics and prognosis were compared within these groups and with conventional de novo appendiceal adenocarcinomas. Both groups A and B tumors shared a similar immunoprofile, which included generally focal immunoreactivity for neuroendocrine markers, and a normal intestinal type mucin glycoprotein profile (negative MUC1 expression and preserved MUC2 immunoreactivity). The proliferative index was relatively low in these tumors and slightly increased from groups A to B tumors (11% to 16%). Both beta-catenin and E-cadherin exhibited a normal membranous staining pattern in groups A and B tumors. The poorly differentiated adenocarcinomas ex GCC (group C) demonstrated abnormal p53 and beta-catenin immunoreactivity. The mean follow-up time was 49+/-5 (SE) months. The overall disease-specific survival for all subtypes was 77%, with 46% of patients without evidence of disease and 31% alive with disease. The mean survival was 43+/-7 months. All the patients with clinical stage of I or IIA disease had a favorable outcome after appropriate surgery with or without chemotherapy. Although most patients (63%) with GCC presented at an advanced clinical stage, their clinical outcome could be differentiated by subclassification of tumors. The stage IV-matched 5-year survival was 100%, 38%, and 0% for groups A, B, and C, respectively. In conclusion, GCC is a distinctive appendiceal neoplasm that exhibits unique pathologic features and clinical behavior. They display a spectrum of histologic features and possess the potential to transform to an adenocarcinoma phenotype of either signet ring cell or poorly differentiated adenocarcinoma types. Careful evaluation of the morphologic features of GCCs and appropriate pathologic classification are crucial for clinical management and prediction of outcome. Surgical management with right hemicolectomy is recommended after appendectomy for most cases, particularly those with an adenocarcinoma component (groups B and C).
Asunto(s)
Adenocarcinoma/patología , Neoplasias del Apéndice/patología , Tumor Carcinoide/patología , Carcinoma de Células en Anillo de Sello/patología , Adenocarcinoma/clasificación , Adenocarcinoma/inmunología , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Apendicectomía , Neoplasias del Apéndice/clasificación , Neoplasias del Apéndice/inmunología , Neoplasias del Apéndice/terapia , Tumor Carcinoide/clasificación , Tumor Carcinoide/inmunología , Tumor Carcinoide/terapia , Carcinoma de Células en Anillo de Sello/clasificación , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/terapia , Diferenciación Celular , Proliferación Celular , Quimioterapia Adyuvante , Colectomía , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Variaciones Dependientes del Observador , Estudios Retrospectivos , Terminología como Asunto , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Among various clinical and pathological findings, lymphatic invasion (Ly) is the strongest risk factor for nodal metastasis in gastric cancer. However, the diagnosis of Ly is subjective and often inaccurate because of the difficulty of detecting lymphatic vessels with conventional hematoxylin and eosin (HE) staining. METHODS: The distribution of lymphatics in the normal gastric wall was immunohistochemically characterized using a new selective marker of lymphatic endothelium, D2-40, in surgical specimens resected for early gastric cancer (EGC). Then, Ly in the primary lesion was reevaluated, and the positive (PPV) and negative (NPV) predictive values for nodal metastasis were comparatively examined for Ly detected by HE staining (Ly-HE) and by immunohistochemical staining (Ly-IM) in 131 cases of EGC. RESULTS: D2-40-positive lymphatic vessels were observed in the deep proper mucosal layer, and the lymphatic vessel density (LVD) was extremely high in the muscularis mucosa (MM) layer. The number of Ly-IM-positive cases (15/131) was higher than the Ly-HE-positive cases (10/131). In 48 cases of intestinal-type cancer, Ly-IM had a PPV of 33.3% (2/6) and anNPV of 100% (42/42), which was more accurate than the corresponding figures for Ly-HE (25% and 98%, respectively). In contrast, the accuracy of Ly-IM was similar to that of Ly-HE in 83 cases of diffuse-type cancer. CONCLUSION: Lymphatic vessels are most densely distributed in the MM layer in the gastric wall. Immunohistochemical identification of lymphatics is useful to increase the accuracy of diagnosing Ly in resected gastric EGCs. Ly-IM is superior to Ly-HE as a predictor of nodal metastasis, at least for intestinal-type EGC.
Asunto(s)
Adenocarcinoma/secundario , Carcinoma de Células en Anillo de Sello/secundario , Ganglios Linfáticos/patología , Neoplasias Gástricas/patología , Adenocarcinoma/inmunología , Adenocarcinoma/cirugía , Anticuerpos Monoclonales , Anticuerpos Monoclonales de Origen Murino , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/cirugía , Endotelio Linfático/patología , Reacciones Falso Positivas , Femenino , Gastrectomía , Humanos , Técnicas para Inmunoenzimas , Metástasis Linfática , Vasos Linfáticos/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Valor Predictivo de las Pruebas , Factores de Riesgo , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/cirugíaRESUMEN
Lewis(y) (Le(y)), also designated CD174, represents a carbohydrate blood group antigen which is strongly expressed in neoplastic gastrointestinal tissues. Previous reports indicated an association between Le(y) expression and apoptosis. Therefore, we tried to elucidate its clinicopathological relevance in a series of 160 gastric and 215 colorectal carcinomas by immunohistochemical detection of Le(y) and visualization of apoptotic cells applying the in-situ-end labelling (ISEL) method, followed by semiquantitative scoring of the specimens. In both gastric as well as colorectal carcinomas, between 40 and 50% of the cases were Le(y) reactive. Signet-ring cell carcinomas of the stomach exhibited a significantly stronger Le(y) expression compared to other tumor types. In colorectal cancers, Le(y) was associated with increased tumor staging, showing the strongest positivity in stage IV. Further correlations with clinicopathological variables or prognosis were not observed. On the other hand, the amount of apoptotic cells was significantly reduced in mucinous adenocarcinomas of the colorectum compared to non-mucinous carcinomas. Scoring of apoptotic cells did not result in any other clinicopathologically relevant correlations. In addition, a significant association between Le(y) antigen expression and apoptosis score could not be established. Therefore, the hypothesis of a functional relationship between these two aspects of gastrointestinal tumor biology is not confirmed by our data.
Asunto(s)
Adenocarcinoma/inmunología , Apoptosis , Carcinoma de Células en Anillo de Sello/inmunología , Neoplasias Colorrectales/inmunología , Antígenos del Grupo Sanguíneo de Lewis/análisis , Neoplasias Gástricas/inmunología , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células en Anillo de Sello/diagnóstico , Carcinoma de Células en Anillo de Sello/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patología , Análisis de SupervivenciaRESUMEN
The latest World Health Organization (WHO) classification divides adenocarcinoma mainly into adenocarcinoma mixed subtypes, acinar adenocarcinoma, papillary adenocarcinoma, bronchioloalveolar carcinoma, and solid adenocarcinoma with mucin production, and it mentions several variants, including fetal adenocarcinoma, mucinous ("colloid") adenocarcinoma, mucinous cystadenocarcinoma, signet-ring adenocarcinoma, and clear cell adenocarcinoma. In general, the mucin-producing adenocarcinoma of the lung comprises signet-ring cell carcinoma (SRCC), solid adenocarcinoma with mucin production (SA), and mucinous bronchioloalveolar carcinoma (m-BAC), mucinous ("colloid") adenocarcinomas and/or mucinous cystadenocarcinoma, and mucoepidermoid carcinoma. As SRCC, SA, and m-BAC exhibit distinct clinical features, it is important to identify differences in their immunohistochemical characteristics to better understand their histogenesis. In this study we analysed SRCC, SA, m-BAC, normal lung, and foregut-related secretory tissue for immunohistochemical differences using tissue microarrays. SRCC and SA showed high expression of MUC1 (97.4% and 100%, respectively), cytokeratin (CK) 7 (both 100%), and thyroid transcription factor-1 (TTF-1) (81.1% and 100%, respectively). They also showed low expression of MUC5AC (25.5% and 21.1%, respectively) and MUC6 (18.3% and 10.5%, respectively), whereas m-BAC showed high expression of MUC5AC (97.5%), MUC6 (75.0%), and CK7 (94.7%), but low expression of MUC1 (57.5%), and TTF-1 (27.5%). Hierarchical clustering showed that the immunophenotypes of SRCC and SA belong to the same category as alveolar lining cells, whereas m-BAC clustered onto another branch with gastric foveolar cells and bronchial goblet cells. These immunohistochemical findings support the results of our previous clinicopathological analysis of SRCC of the lung showing that SRCC occurs anatomically in the peripheral portion of the lung rather than in the bronchial gland-bearing portion.
Asunto(s)
Adenocarcinoma/inmunología , Neoplasias Pulmonares/inmunología , Mucinas/metabolismo , Proteínas de Neoplasias/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma Bronquioloalveolar/inmunología , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Mucinoso/inmunología , Adenocarcinoma Mucinoso/metabolismo , Carcinoma de Células en Anillo de Sello/inmunología , Carcinoma de Células en Anillo de Sello/metabolismo , Humanos , Técnicas para Inmunoenzimas , Inmunofenotipificación , Neoplasias Pulmonares/metabolismo , Análisis por Matrices de Proteínas/métodosRESUMEN
SUMMARY: We previously reported acid-extracted natural antigenic peptide (F4.2 [YSWMDISCWI]) of a gastric signet ring cell carcinoma HST-2 cells, recognized by HLA-A*31012-restricted autologous cytotoxic T lymphocytes, TcHST-2 line. In this study, the full-length cDNA (1101 bp), termed c98, predicting a protein composed of 170 amino acids was obtained. Because TcHST-2 cells could lyse the HLA-A31 antigen (+) allogeneic tumor cells that were introduced with c98 gene, this gene was suggested to possess antigenicity. Beginning at N-terminal 61 amino acid, the N-terminal six amino acid sequence that is completely identical to F4.2 was present in c98; however, a sequence of four amino acids in C-terminal was not found. Nevertheless, this peptide, c98(61-70), seemed to be immunogenic, because cells pulsed with c98(61-70) peptide were lysed in a dose-dependent manner by TcHST-2 cells. The c98 gene was expressed ubiquitously in tumor cells as well as in normal tissues. However, some tumor cells, including HST-2 cells, expressed this antigen in a high content, and such cells were lysed by TcHST-2 cells in the context of HLA-A31 antigen. However, TcHST-2 cells did not lyse cells that expressed lower amounts of c98 than HST-2 cells. These data suggested that c98-gene product and/or c98(61-70) peptides could be used as a candidate for tumor vaccines in cancer immunotherapy.